rs1341863

Variant names:

• chr1-236720121-C-T
• rs1341863
• NM_001103.4:c.378C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001103.4(ACTN2):​c.378C>T​(p.Asn126Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.98 in 1,611,842 control chromosomes in the GnomAD database, including 776,125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (66858 hom., cov: 33)
  • Exomes 𝑓: 0.99 (709267 hom.)
• Consequence: ACTN2 NM_001103.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.102
• Publications: 22 publications found

Genes affected

ACTN2 (HGNC:164): (actinin alpha 2) Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a muscle-specific, alpha actinin isoform that is expressed in both skeletal and cardiac muscles. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2013]

ACTN2 Gene-Disease associations (from GenCC):

• intrinsic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Laboratory for Molecular Medicine, ClinGen
• myopathy, congenital, with structured cores and z-line abnormalities

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy 1AA

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• heart conduction disease

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• myopathy, distal, 6, adult-onset, autosomal dominant

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Broad Center for Mendelian Genomics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 1-236720121-C-T is Benign according to our data. Variant chr1-236720121-C-T is described in ClinVar as Benign. ClinVar VariationId is 43938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.102 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.989 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001103.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN2	NM_001103.4	MANE Select	c.378C>T	p.Asn126Asn	synonymous	Exon 4 of 21	NP_001094.1
	ACTN2	NM_001278343.2		c.378C>T	p.Asn126Asn	synonymous	Exon 4 of 21	NP_001265272.1
	ACTN2	NR_184402.1		n.553C>T		non_coding_transcript_exon	Exon 4 of 23

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN2	ENST00000366578.6	TSL:1 MANE Select	c.378C>T	p.Asn126Asn	synonymous	Exon 4 of 21	ENSP00000355537.4
	ACTN2	ENST00000542672.7	TSL:1	c.378C>T	p.Asn126Asn	synonymous	Exon 4 of 21	ENSP00000443495.1
	ACTN2	ENST00000682015.1		c.378C>T	p.Asn126Asn	synonymous	Exon 4 of 20	ENSP00000506961.1

Frequencies

GnomAD3 genomes AF: 0.934 AC: 142084 AN: 152138 Hom.: 66832 Cov.: 33

Gnomad AFR AF: 0.814

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.897

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 0.985

Gnomad SAS AF: 0.970

Gnomad FIN AF: 0.987

Gnomad MID AF: 0.975

Gnomad NFE AF: 0.996

Gnomad OTH AF: 0.948

GnomAD2 exomes AF: 0.961 AC: 241683 AN: 251374 AF XY: 0.968

Gnomad AFR exome AF: 0.817

Gnomad AMR exome AF: 0.871

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 0.980

Gnomad FIN exome AF: 0.988

Gnomad NFE exome AF: 0.995

Gnomad OTH exome AF: 0.971

GnomAD4 exome AF: 0.985 AC: 1437881 AN: 1459586 Hom.: 709267 Cov.: 35 AF XY: 0.986 AC XY: 715849 AN XY: 726288

African (AFR) AF: 0.808 AC: 27022 AN: 33426

American (AMR) AF: 0.872 AC: 39014 AN: 44720

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26116 AN: 26124

East Asian (EAS) AF: 0.984 AC: 39030 AN: 39670

South Asian (SAS) AF: 0.971 AC: 83728 AN: 86200

European-Finnish (FIN) AF: 0.989 AC: 52835 AN: 53416

Middle Eastern (MID) AF: 0.985 AC: 5675 AN: 5764

European-Non Finnish (NFE) AF: 0.996 AC: 1105522 AN: 1109962

Other (OTH) AF: 0.977 AC: 58939 AN: 60304

GnomAD4 genome AF: 0.934 AC: 142161 AN: 152256 Hom.: 66858 Cov.: 33 AF XY: 0.933 AC XY: 69421 AN XY: 74444

African (AFR) AF: 0.814 AC: 33752 AN: 41488

American (AMR) AF: 0.896 AC: 13708 AN: 15292

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 0.985 AC: 5105 AN: 5184

South Asian (SAS) AF: 0.970 AC: 4688 AN: 4834

European-Finnish (FIN) AF: 0.987 AC: 10478 AN: 10618

Middle Eastern (MID) AF: 0.973 AC: 286 AN: 294

European-Non Finnish (NFE) AF: 0.996 AC: 67754 AN: 68048

Other (OTH) AF: 0.949 AC: 2006 AN: 2114

Alfa AF: 0.975 Hom.: 110216

Bravo AF: 0.921

Asia WGS AF: 0.963 AC: 3351 AN: 3478

EpiCase AF: 0.996

EpiControl AF: 0.995

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Myopathy, congenital, with structured cores and z-line abnormalities (1)
-	-	1	not provided (1)
-	-	1	Primary familial hypertrophic cardiomyopathy;C2677338:Dilated cardiomyopathy 1AA (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	1.6
DANN	Benign	0.67
PhyloP100		-0.10
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1341863; hg19: chr1-236883421; COSMIC: COSV108199735;